Links between electroconvulsive therapy responsive and cognitive impairment multimodal brain networks in late-life major depressive disorder

Background: Although electroconvulsive therapy (ECT) is an effective treatment for depression, ECT cognitive impairment remains a major concern. The neurobiological underpinnings and mechanisms underlying ECT antidepressant and cognitive impairment effects remain unknown. This investigation aims to identify ECT antidepressant-response and cognitive-impairment multimodal brain networks and assesses whether they are associated with the ECT-induced electric field (E-field) with an optimal pulse amplitude estimation. Methods: A single site clinical trial focused on amplitude (600, 700, and 800 mA) included longitudinal multimodal imaging and clinical and cognitive assessments completed before and immediately after the ECT series (n = 54) for late-life depression. Another two independent validation cohorts (n = 84, n = 260) were included. Symptom and cognition were used as references to supervise fMRI and sMRI fusion to identify ECT antidepressant-response and cognitive-impairment multimodal brain networks. Correlations between ECT-induced E-field within these two networks and clinical and cognitive outcomes were calculated. An optimal pulse amplitude was estimated based on E-field within antidepressant-response and cognitive-impairment networks. Results: Decreased function in the superior orbitofrontal cortex and caudate accompanied with increased volume in medial temporal cortex showed covarying functional and structural alterations in both antidepressant-response and cognitive-impairment networks. Volume increases in the hippocampal complex and thalamus were antidepressant-response specific, and functional decreases in the amygdala and hippocampal complex were cognitive-impairment specific, which were validated in two independent datasets. The E-field within these two networks showed an inverse relationship with HDRS reduction and cognitive impairment. The optimal E-filed range as [92.7-113.9] V/m was estimated to maximize antidepressant outcomes without compromising cognitive safety. Conclusions: The large degree of overlap between antidepressant-response and cognitive-impairment networks challenges parameter development focused on precise E-field dosing with new electrode placements. The determination of the optimal individualized ECT amplitude within the antidepressant and cognitive networks may improve the treatment benefit-risk ratio.

Automated summary

This study identifies the multimodal brain networks associated with ECT antidepressant-response and cognitive-impairment and explores the correlation between these networks and the ECT-induced electric field (E-field). The findings suggest that changes in the superior orbitofrontal cortex, caudate, and medial temporal cortex are common to both antidepressant-response and cognitive-impairment networks. Additionally, specific alterations in the hippocampal complex, thalamus, amygdala, and hippocampal complex are associated with either antidepressant-response or cognitive-impairment. The E-field within these networks shows an inverse relationship with HDRS reduction and cognitive impairment. The optimal E-field range for maximizing antidepressant outcomes without compromising cognitive safety is estimated to be [92.7-113.9] V/m.